The human SMYD (SET and MYND domain-containing protein) family of protein lysine methyltransferases contains five members (SMYD1-5). The role each of these protein lysine methyltransferases play in the development of cancer have been the focus of extensive study to-date. In particular, SMYD2 has been shown to methylate both histone (H2B, H3, and H4) and nonhisione protein substrates, including the tumor suppressor proteins p53 and Rb. (See, e.g., Ferguson et al., Structure, vol. 19, pp. 1262-1273 (2011); Komatsu et al., Carcinogenesis, vol. 30, pp. 1139-1146 (2009); and, Huang et al., Nature, vol. 444, pp. 629-632 (2006).) Methylation of K370 of p53 impairs its ability to bind to the promoters of target genes. Methylation of Rb at residue K860 generates an epitope that is selectively recognized by the transcriptional repressor L3MBTL1. This may provide a mechanism for recruiting L3MBTL1 to the promoters of specific Rb/E2F target genes, thereby repressing their activities. In addition to these established biological pathways, the SMYD2 gene lies in the 1q32-q41 region, which is frequently amplified in esophageal squamous cell carcinoma (ESCC) and other solid tumors. Overexpression of SMYD2 is observed in the esophageal cell line KYSE150, and in ESCC primary tumor samples. Genetic knockdown of SMYD2 leads to decreased ESCC cell proliferation.
Protein lysine methyltransferases have emerged as attractive targets for drug discovery. As a result, there are ongoing efforts to identify chemical starting points for this novel class of enzymes. Given the activity of SMYD2 in ESCC cells, and that its protein substrates, including the key tumor suppressors p53 and Rb, have been implicated in gene transcription, apoptosis, and cell cycle regulation, there is a need for the development of small molecule inhibitors of SMYD2.